Synapse-specific and developmentally regulated targeting of AMPA receptors by a family of MAGUK scaffolding proteins
Synapse-specific and developmentally regulated targeting of AMPA receptors by a family of MAGUK scaffolding proteins
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DOI：
10.1016/j.neuron.2006.09.012
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发表时间：
2006-10-19
期刊：
影响因子：
16.2
通讯作者：
Nicoll, Roger A.
中科院分区：
文献类型：
--
作者：
Elias, Guillermo M.;Funke, Lars;Nicoll, Roger A.
AMPA受体(AMPA受体)进出突触的运输控制着兴奋性突触传递的强度。然而，聚集在突触上的AMPA-R的蛋白质仍然知之甚少。在这里，我们证明了PSD-95样膜相关鸟苷酸晚期蛋白(PSD-MAGUKs)介导了这种突触靶向，我们发现该蛋白家族中存在显著的功能冗余。通过操纵内源性神经元PSD-Maguk水平，我们发现PSD-95和PSD-93都独立地介导AMPA-R靶向成熟突触。我们还揭示了突触的异质性，如PSD-95或PSD-93沉默的丧失，大部分不重叠的兴奋性突触群体。在成年PSD-95和PSD-93双基因敲除动物中，SAP-102上调并补偿突触AMPA-R的丢失。在未成熟突触中，PSD-95和PSD-93在突触AMPA-R聚集中的作用很小；相反，SAP-102占主导地位。这些研究建立了PSD-Maguk对AMPA-R突触表达的特异性调节，从而在哺乳动物中枢神经系统中建立和维持谷氨酸能突触传递。
Trafficking of AMPA receptors (AMPA-Rs) to and from synapses controls the strength of excitatory synaptic transmission. However, proteins that cluster AMPA-Rs at synapses remain poorly understood. Here we show that PSD-95-like membrane-associated guanylate kinases (PSD-MAGUKs) mediate this synaptic targeting, and we uncover a remarkable functional redundancy within this protein family. By manipulating endogenous neuronal PSD-MAGUK levels, we find that both PSD-95 and PSD-93 independently mediate AMPA-R targeting at mature synapses. We also reveal unanticipated synapse heterogeneity as loss of either PSD-95 or PSD-93 silences largely nonoverlapping populations of excitatory synapses. In adult PSD-95 and PSD-93 double knockout animals, SAP-102 is upregulated and compensates for the loss of synaptic AMPA-Rs. At immature synapses, PSD-95 and PSD-93 play little role in synaptic AMPA-R clustering; instead, SAP-102 dominates. These studies establish a PSD-MAGUK-specific regulation of AMPA-R synaptic expression that establishes and maintains glutamatergic synaptic transmission in the mammalian central nervous system.